Fig.37.5 ).Forexample,aGprotein–coupledH+ receptor(GPCR–GPR4)hasbeenlocalizedtothecollectingduct.ActivationofthisreceptorbyanincreaseinECF[H+]stimulatesH+ secretion.Alsointhecollectingduct,HCO3−-secretingintercalatedcells(B-orβ-ICs)expressabasolateralinsulin-relatedreceptor(IRR)thatisatyrosinekinase.ItisactivatedbyanincreaseinECF[HCO3−]andstimulatesHCO3− secretionbythecell.Asolubleadenylylcyclase(sAC)regulatedbyintracellularHCO3− appearstoalsoplayarollinregulatingcollectingductH+ secretion.Intheproximaltubule,basolateralmembranereceptortyrosinekinases(ErbB1andErbB2)sensechangesinECFPCO2.ActivationofthesereceptorsbyanincreaseinPCO2resultsingenerationofangiotensinII,whichactingfromthelumenviaAT-1Areceptors,stimulatesH+ secretion/HCO3− reabsorption.Alsointheproximaltubule,thenonreceptortyrosinekinase(Pyk2)sensesintracellular[H+].Whenitisactivatedbyanincreaseinintracellular[H+],H+ secretion/HCO3− reabsorptionisstimulated.Finally,thegatingofseveralionchannels(e.g.,therenaloutermedullaryK+ channel[ROMK])iseffectedbychangesineitherECForICFpH.Thesetoohavethepotentialtoserveascellularacid-basesensors.
Although some of the effects just described may be attributable directly to acidosis, many of these changes in cellular H+ transport are mediated by hormones or other factors. Three known mediators of the renal response to acidosis are endothelin, cortisol, and angiotensin II. Endothelin (ET-1)
Intheproximaltubule,metabolicacidosisincreasesthetransportkineticsoftheNa+/H+ antiporter(NHE3)andincreasesapicalmembraneexpressionoftheNa+/H+ antiporter,H+-ATPase,andthebasolateralNa+/3HCO3− symporter(NBCe1).Inthecollectingduct,acidosisleadstoexocyticinsertionofH+-ATPaseintotheapicalmembraneofintercalatedcells.Withlong-termacidosistheabundanceofkeyacid-basetransportersisincreasedintheproximaltubule(NHE3andNBCe1)andincollectingductintercalatedcells(H+-ATPaseandAE1).Lastly,acidosisdecreasesexpressionoftheCl−/HCO3− antiporterpendrininHCO3−-secretingintercalatedcells.